AraC-FdUMP[10] Is a Next-Generation Fluoropyrimidine with Potent Antitumor Activity in PDAC and Synergy with PARG Inhibition
Open Access
- 16 February 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 19 (4), 565-572
- https://doi.org/10.1158/1541-7786.mcr-20-0985
Abstract
AraC-FdUMP[10] (CF10) is a second-generation polymeric fluoropyrimidine that targets both thymidylate synthase (TS), the target of 5-fluorouracil (5-FU), and DNA topoisomerase 1 (Top1), the target of irinotecan, two drugs that are key components of FOLFIRNOX, a standard-of-care regimen for pancreatic ductal adenocarcinoma (PDAC). We demonstrated that F10 and CF10 are potent inhibitors of PDAC cell survival (in multiple cell lines including patient-derived lines) with IC50s in the nanomolar range and are nearly 1,000-fold more potent than 5-FU. The increased potency of CF10 relative to 5-FU correlated with enhanced TS inhibition and strong Top1 cleavage complex formation. Furthermore, CF10 displayed single-agent activity in PDAC murine xenografts without inducing weight loss. Through a focused drug synergy screen, we identified that combining CF10 with targeting the DNA repair enzyme, poly (ADP-ribose) glycohydrolase, induces substantial DNA damage and apoptosis. This work moves CF10 closer to a clinical trial for the treatment of PDAC.Implications:. CF10 is a promising polymeric fluoropyrimidine with dual mechanisms of action (i.e., TS and Top1 inhibition) for the treatment of PDAC and synergizes with targeting of DNA repair.Other Versions
Funding Information
- NIH NCI (R21CA218933)
- NIH NCI (R01CA212600-01)
- NIH (U01CA224012)
- NIH (P30CA069533)
- NIH (P30CA056036)
- Pancreatic Cancer Action Network-AACR Research Acceleration Network Grant (15-90-25-BROD)
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